Hemophilia A

Most common inherited coagulation protein deficiency with an occurrence of approximately 1 in 10,000 live births, 1 in 5,000 live male births or 20.6 per 100,000 males in the U.S.

A bleeding disorder resulting from decreased or absent Factor VIII which regulates thrombin generation.

Prevalence of 17.1 cases per hundred thousand males, it is the most frequently inherited disorder of blood coagulation.

Transmitted deficiency of Factor VIII via an X-linked recessive manner.

Spontaneous mutation of X chromosome accounts for 30% of cases without a family history.

If the adoption of prophylactic replacement therapy with factor VIII life expectancy has become very close to that of unaffected males.

The degree of bleeding experienced by the patient correlates with Factor VIII levels.

Mild, moderate and severe deficiencies correlate with Factor VIII activity of 5-20%, 1-5% and less than 1% of normal, respectively.

Hemorrhage into muscles, soft tissues, joints and bleeding from mucosal surfaces are typical findings.

Recurrent hemorrhage into joints leads to synovial scarring and cartilage destruction with deformation and joint function compromise.

Life expectancy about 65 years.

Prolonged partial thromboplastin time (PTT) in the face of normal prothrombin time.

Increased partial thromboplastin time corrects with mixing studies with normal pooled plasma.

Associated with a normal bleeding time, platelet aggregation studies, and normal von Willebrand factor antigen and activity.

In severe Hemophilia A functional clotting factor VIII levels of <0.01 IU per mL associated with bleeding into joints and muscles.

With severe hemophilia A detection of inversions of intron 22 occurs in 40-45% of patients and intron 1 in 1-6% of patients with severe disease of the F8 gene are the most common mutations.

Mainstay of treatment is the replacement of Factor VIII to levels that support normal hemostasis.

Traditional treatment involves replacing deficient clotting factors to restore hemostasis, and prophylaxis is now the standard of care.

Study of hemarthrosis of children with various severities of hemophilia reveal that joint bleeding approaches zero only in children with baseline factor. VIII levels above 12%.

Prophylactic injections of recombinant factor VIII reduces risk of bleeds in children with hemophilia.

To prevent joint destruction in severely deficient children primary prophylaxis, including regular infusions of factor VIII are initiated at the time of first episode of joint bleeding, or earlier to prevent joint damage.

Administration of 85IU/ kg of recombinant factor VIII weekly reduces incidence of all bleeds in children by 82% (Manco-Johnson MJ et al).

Administration of 75IU/kg of recombinant factor VIII weekly reduces bleeds by 48% (Gringeri A et al).

In moderate to mild disease DDAVP, a synthetic vasopressin analog, increases Factor VIII release from storage pools.

At the time of initial diagnosis of mild-moderate disease a DDAVP trial is performed with analysis of factor VIII activity before and 1 hour after intravenous infusion of 0.3 µg/kg of desmopressin or intranasal desmopressin, which will determine its usefulness in management of subsequent minor hemorrhage.

The standard treatment for severe hemophilia a is a trough factor VIII level of 1 international unit per deciliter or 1%.

Many use a target trough factor VIII activity of 3 to 5 IU per deciliter or higher for their patients.

Factor VIII levels of 25-30% of normal are usually adequate to treat minor bleeding episodes including spontaneous hemarthroses and dental procedures.

Factor VIII levels of 80-100% of normal activity levels needed for life threatening bleeding events, major surgery, visceral or intramuscular bleeding.

Rarely mild hemophilia A with autosomal inheritance may reflect type 2N von Willebrand disease with mutations in the factor VIII binding domain of von Willebrand factor.

The dose of Factor VIII needed for replacement therapy can be calculated by assuming each unit of Factor VIII administered per kilogram of body weight will raise the plasma Factor VIII activity by 2%.

The interaction between factor VIII, and endogenous von Willebrand factor imposes a ceiling of 8 to 19 hours on the half-life of current factor VIII replacement products.

The maintenance factor VIII levels in the normal range of 50 to 150 international units per deciliter, or levels close to normal of greater than 4o-50 IU per deciliter with currently available factor VIII therapies requires frequent administration, which confers  avsubstantial treating burden of people with hemophilia.

For surgery Factor VIII is given prior to the procedure and is continued at lower doses to achieve 50% factor level for 7-14 days to ensure adequate wound healing.

Continuous infusion of Factor VIII at 2 units/kg/hour with titration to maintain the desired factor VIII level reduces bleeding complications and peaks and troughs of bolus therapy and decreases factor consumption.

No differences exist for clinical efficacy between recombinant Factor VIII or plasma-derived Factor VIII.

For prophylaxis and treatment of surgical treatments and major bleeding bolus, or continuous intravenous infusions of factor VIII are standard of care.

Treatment is the prophylactic management to increase factor VIII levels through intervenous administration of clotting factor or, the substitution effect VIII function through subcutaneous administration of the humanized bispecific monoclonal  antibody Emicizumab.

Factor replacement has therapeutic challenges: intravenous access, incomplete bleeding protection, infusion frequency, and inhibitor development.
Clinical improvements are due to extended half-life products, factor VIII mimetics, rebalancing agents, and gene therapy.

Plasma-derived Factor VIII associated with transmission of hepatitis A and parvovirus B19.Cryoprecipitate not indicated for treatment unless Factor VIII concentrates not available in an emergency situation.

Acquired hemophilia is rare and is caused by autoantibody to factor VIII.

Acquired disease associated bleeding disorder can be treated with factor VIII, recombinant factor VIIa, and factor 8 inhibitor bypassing activity (FEIBA).

Acquired hemophilia patients usually older and have a higher incidence of associated malignancy.

Acquired hemophilia bleeding pattern differs from patients with congenital type disease with marked variation in bleeding symptoms and about one third of patients requiring no hemostatic treatment and approximately 8% experiencing fatal bleeds (Collins at al).

Acquired antibodies to factor VIII associated with pregnancy, autoimmune disease, and malignancy.

Acquired hemophilia A associated with hematologic malignancies, and included diagnoses of chronic lymphocytic leukemia, erythroleukemia, myelofi brosis, multiple myeloma and myelodysplastic syndrome. 

In these patients, the appearance of the inhibitor preceded the diagnosis of the underlying malignancy by an average of 3.5 months. 

In about 30% of children inhibitory antibodies to factor VIII develop and make usual treatment with factor VIII and prophylaxis impossible.

Recombinant and plasma derived factor VIII confer similar risks of inhibitor development (Gouw SC et al).

Death is more frequent within the first few weeks after finding of symptomatic manifestation of acquired hemophilia, making rapid diagnosis and treatment essential.

Acquired hemophilia treatment is focused on stabilization of initial bleeding and long-term eradication of the acquired inhibitor.

As many as 50% of adults abandon prophylactic treatment due to invasiveness and inconvenience, and 25%-30%  develop inhibitory antibodies.

Gene therapy with AAV5-hFVIII-SQ vector in patients with heophilia A resulted in sustained benefit with substantial reduction in annualized rates of bleeding events a complete cessation of prophylactic factor III use in all participants who received such therapy. (Pasi KJ).

In patients with severe hemophilia A Valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis (GENEr8-1 Trial Group): at 2 years factor VIII activity and bleeding episodes is similar to that reported with the use of data from persons with mild to moderate hemophilia A.

Factor VIII products with extended plasma half life minimizes bleeding and can be administered now intravenously twice weekly.
Emicizumab a monoclonal antibody mimics factor VIII coagulant activity and is efficacious preventing bleeding when administered subcutaneously weekly or even every two week intervals.

Emicizumab is a  bispecific monoclonal antibody mimicking activated factor VIII which has improved outcomes for patients with hemophilia A, but has not eliminated breakthrough bleeding.

Efanesoctocog alpha is a factor a replacement therapy designed to decouple recombinant factor VIII from endogenous Willebrand’s factor and overcome  the VWF imposed half life ceiling.

Efanesoctocog alpha in severe hemophilia A provided once weekly had superior bleeding prevention to pre-study prophylaxis, normal to near normal factor VIII activity and improvements in physical health, pain, and joint health.

Adenovirus associated mediated gene transfer for factor  VIII with valoctogene roxaparvovec therapy has been found to be efficacious.



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